Our long-term goal is to understand the mechanisms that control the growth, differentiation, and regeneration of the liver. Epidermal growth factor (EGF) and its homolgs are arguably the most thoroughly studied growth factors in the control of liver growth, regeneration and carcinogenesis. However, the relationship of EGF to the liver is far more complex than ever imagined, since we now know that there are dozens of EGF-like molecules and that they act through four different receptors, the ErbB proteins. A vast diversification of signaling is affected through these receptors depending not only on which ligands are present, but also upon which combinations of receptors are available for recruitment into signaling complexes. This study focuses on the role played by the ErbB receptors as regulators of growth and differentiation in the liver. We have documented different ErbB signaling interactions in fetal and adult liver. We have also discovered that the potent hepatic mitogen, HGF, exerts its proliferative actions in hepatocytes by activating ErbB receptors. The specific aims of this proposal are to: 1. Define the developmental role of ErbB2 in the regulation of liver growth and differentiation; 2. Define the role of the EGF receptor in mitogenic signaling in the liver and the extent to which it's known effects involve co-signaling with ErbB2 and ErbB3; and 3. Evaluate the central role of ErbB proteins as signal transducers for HGF. Progress toward these aims will improve our understanding of how EGF-like molecules signal in a normal tissue, how the liver differentiates into its adult functional form, and how these potent mitogens regulate the dramatic restoration of liver mass during regeneration. Liver regeneration is a paradigm for other conditions of normal or altered growth regulation, including tissue hypertrophy, wound healing, and cancer. In addition to elucidating the mechanisms of growth control in the liver, our studies may ultimately aid in the generation of mature hepatocytes from undifferentiated stems cells for transplantation and for the generation of artificial livers. [unreadable] [unreadable]